Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis (SATELITE)

February 6, 2023 updated by: Assistance Publique - Hôpitaux de Paris

Salvage Therapy for Patients With Inadequate Response to Standard of Care Therapy in Granulomatosis With Polyangiitis

The purpose of this study is to identify the most promising therapeutic strategy for patients with granulomatosis with polyangiitis and inadequate response to standard of care therapy. It will evaluate the efficacy to induce remission of three different salvage strategies including: a combination of rituximab with addition of a conventional disease-modifying antirheumatic drugs (either methotrexate, azathioprine or mycophenolate mofetil, but preferentially methotrexate); tocilizumab; or abatacept.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Granulomatosis with polyangiitis (GPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).

Combination of glucocorticoids and either cyclophosphamide or rituximab is the standard of care for remission-induction of new-onset organ-threatening or life-threatening GPA. Few patients fail to respond to both cyclophosphamide and rituximab, but it is not uncommon for patients to have persistent disease activity resulting in inability to taper glucocorticoids, which is also considered refractory disease. The current recommendations for patients with GPA refractory to remission-induction therapy are to switch from cyclophosphamide to rituximab or from rituximab to cyclophosphamide. However, there are no recommendations for the management of patients with inadequate response after both treatments. Treatment with a biologic disease-modifying antirheumatic drugs (DMARD) or a combination of rituximab and a cDMARD are potential treatments options but have not been properly evaluated in such cases. Among biologic DMARD that have been evaluated in AAV, some have shown promising results, including tocilizumab and abatacept.

Identifying the most promising therapeutic strategy for patients with GPA and inadequate response to standard of care therapy may improve management of GPA.

Study Type

Interventional

Enrollment (Anticipated)

42

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75020
        • Hopital de la Croix Saint Simon

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Newly diagnosed or relapsing granulomatosis with polyangiitis according to American College of Rheumatology criteria, EMA classification algorithm and/or the 2012 revised Chapel Hill Consensus Conference definition.
  • Aged 18 years or older
  • Active clinical manifestations attributable to GPA

  • An inadequate response to previous standard of care therapy including

    1. Both a combination of glucocorticoids plus cyclophosphamide and a combination of glucocorticoids plus rituximab
    2. Or an inadequate response to a combination of glucocorticoids plus rituximab and a contraindication to cyclophosphamide

  • An inadequate response to treatment defined as follows:

    1. A progressive disease unresponsive to previous standard of care therapy after 12 weeks of treatment
    2. Or a lack of response, defined as < 50% reduction in the disease activity score, after 12 weeks of treatment
    3. Or a persistent active disease attributable to either a vasculitic or a granulomatous manifestation of GPA that requires the maintenance of corticosteroids ≥ 7.5 mg/day of equivalent prednisone after ≥ 12 weeks of treatment.
  • A stable dose of oral glucocorticoids of ≥ 7.5 mg/day of equivalent prednisone within the 4 weeks before enrollment. Pulses of methylprednisolone (1 to 3 pulses of 7.5 to 15 mg/kg each; ≤ 1000 mg) are allowed if necessary, according to severity before starting the experimental treatment.
  • A stable dose of conventional disease-modifying anti-rheumatic drugs (cDMARD) within 4 weeks before enrollment if the patient is currently treated with a cDMARD
  • Patients must have the ability to understand the requirements of the study, provide written informed consent prior to participation in the study (including consent for the use and disclosure of research-related health information) and comply with the study protocol procedures (including required study visits)
  • Patients must have an affiliation with a mode of social security (profit or being entitled)

Exclusion Criteria:

  • An allergy or hypersensitivity to monoclonal antibodies or either of the study drugs (rituximab, abatacept or tocilizumab) or to their excipients
  • A previous treatment with a combination of rituximab plus a cDMARD, with abatacept, or with tocilizumab
  • A contraindication to a combination of rituximab plus a cDMARD, to abatacept, or to tocilizumab (including an ongoing infection; history of recent cancer <5 years before enrollment, except for cured non-melanoma skin cancer); pregnancy; and breastfeeding.
  • Patients with severe vasculitis manifestations that requires plasma exchange therapy including severe renal failure with a creatinine level ≥350 µmol/L or severe alveolar haemorrhage
  • Patients with vasculitis in remission
  • Patients with symptoms attributable to chronic and non-active GPA
  • Patients with severe cardiac failure defined as class IV in New York Heart Association
  • Patients with acute infections or chronic active infections (including HIV, HBV or HCV)
  • Patients with active cancer or recent cancer (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment
  • Pregnant women and lactation. All women with childbearing potential are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective contraception from the date of consent through the end of the study, and for women who are taking abatacept through 14 weeks after the last treatment administration, for women who are taking tocilizumab through 3 months after the last treatment administration, for women who are taking rituximab in combination with methotrexate through 6 months after the last treatment administration, for women who are taking rituximab in combination with mycofenolate mofetil or with azathioprine through 3 months after the last treatment administration
  • Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol
  • Patients included in other investigational therapeutic study within the previous 3 months
  • Patients suspected not to be observant to the proposed treatments

  • Laboratory parameter exclusions

    1. aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) > 5 times upper limit of normal
    2. Platelet count <100.000/mm3
    3. White blood cell count <2000/mm3

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: SINGLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Rituximab + cDMARD
Rituximab will be administered at 375 mg/m²/week for four consecutive weeks. Maintenance rituximab at a fixed dose of 500 mg will be administered at week 24 and at week 52. The choice of the cDMARD will be left to the treating clinician and will include either methotrexate, azathioprine or mycophenolate mofetil, but the choice will be preferably methotrexate. Methotrexate will be administered orally or subcutaneously at 0.3 mg/kg/week, azathioprine orally at 2-3 mg/kg/d and mycophenolate mofetil orally at 2-3 g/d.
Drug: Rituximab
375 mg/m²/week for four consecutive weeks (Week 0, 1, 2 and 3) Maintenance rituximab at a fixed dose of 500 mg will be administered at week 24 and at week 52.
Other Names:
  • Mabthera
EXPERIMENTAL: Tocilizumab
Tocilizumab will be administered subcutaneously every week at a fixed dose of 162 mg per week.
Drug: Tocilizumab
Subcutaneous injection of 162 mg per week
Other Names:
  • RoActemra
EXPERIMENTAL: Abatacept
Abatacept will be administered subcutaneously every week at a fixed dose of 125 mg per week.
Drug: Abatacept
Subcutaneous injection of 125 mg per week
Other Names:
  • Orencia

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients with a response or a remission
Time Frame: week 12
defined according to the EULAR recommendations. Remission is defined as the absence of disease activity attributable to active disease qualified by the need for ongoing stable maintenance immunosuppressive therapy. The term ''active disease'' is not restricted to vasculitis only, but also includes other inflammatory features like granulomatous inflammation. Response is defined as a 50% reduction of disease activity score and absence of new manifestations.
week 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients with a response or a remission at week 26 and 52.
Time Frame: week 26 and 52
according to the EULAR recommendations
week 26 and 52
Physician's and patient's global assessment of disease activity
Time Frame: week 12 and 52
The difference between the physician's and patient's global assessment of disease activity between baseline and week 12 and between baseline and week 52 using a scale ranging from 0 to 100, with higher scores indicating more activity.
week 12 and 52
Patient-reported outcomes
Time Frame: week 12, 24 and 52
The patient-reported outcomes (PRO) including the ANCA-associated vasculitis patient-reported outcomes (AAV-PRO) questionnaire, a 29-item profile measure comprising six domains, with higher scores meaning more active disease, at week 12, 24, and 52 after randomization, and during the long-term follow-up.
week 12, 24 and 52
Adverse events
Time Frame: week 26 and 52
The number of adverse events, expressed as adverse events according to the CTCAE toxicity grading system per patient-year at week 26 and 52 for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorrhagic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions
week 26 and 52
Corticosteroids use
Time Frame: week 26 and 52
The area under the curve for corticosteroids at week 26 and 52
week 26 and 52
Vasculitis Damage Index
Time Frame: week 26 and 52
The Vasculitis Damage Index (VDI, scoring from 0 to 58, higher scores indicating more damage) at week 26 and 52
week 26 and 52
Health Assessment Questionnaire (HAQ)
Time Frame: week 26 and 52
ranging from 0 to 3, with higher scores indicating worse functional impairment
week 26 and 52
Short Form 36 (SF-36) Health questionnaire
Time Frame: week 26 and 52
scores range from 0 to 100 for each component, with lower scores indicating greater impairment of quality of life
week 26 and 52
ANCA titers
Time Frame: week 26 and 52
Evolution of ANCA titers in the treatment groups
week 26 and 52

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

URC-CIC Paris Descartes Necker Cochin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

March 1, 2023

Primary Completion (ANTICIPATED)

September 1, 2026

Study Completion (ANTICIPATED)

January 1, 2027

Study Registration Dates

First Submitted

February 26, 2021

First Submitted That Met QC Criteria

May 3, 2021

First Posted (ACTUAL)

May 4, 2021

Study Record Updates

Last Update Posted (ACTUAL)

February 8, 2023

Last Update Submitted That Met QC Criteria

February 6, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P200026

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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